US4802101A - Signal processing method for determining base sequence of nucleic acid - Google Patents
Signal processing method for determining base sequence of nucleic acid Download PDFInfo
- Publication number
- US4802101A US4802101A US06/897,999 US89799986A US4802101A US 4802101 A US4802101 A US 4802101A US 89799986 A US89799986 A US 89799986A US 4802101 A US4802101 A US 4802101A
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- band
- autoradiograph
- signal processing
- processing method
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- 108020004707 nucleic acids Proteins 0.000 title claims abstract description 23
- 150000007523 nucleic acids Chemical class 0.000 title claims abstract description 23
- 102000039446 nucleic acids Human genes 0.000 title claims abstract description 23
- 238000003672 processing method Methods 0.000 title claims abstract description 17
- 239000012634 fragment Substances 0.000 claims abstract description 34
- 239000000203 mixture Substances 0.000 claims abstract description 17
- 238000012545 processing Methods 0.000 claims abstract description 16
- 230000002285 radioactive effect Effects 0.000 claims abstract description 10
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 claims description 22
- OPTASPLRGRRNAP-UHFFFAOYSA-N cytosine Chemical compound NC=1C=CNC(=O)N=1 OPTASPLRGRRNAP-UHFFFAOYSA-N 0.000 claims description 8
- UYTPUPDQBNUYGX-UHFFFAOYSA-N guanine Chemical compound O=C1NC(N)=NC2=C1N=CN2 UYTPUPDQBNUYGX-UHFFFAOYSA-N 0.000 claims description 8
- 239000000463 material Substances 0.000 claims description 8
- RWQNBRDOKXIBIV-UHFFFAOYSA-N thymine Chemical compound CC1=CNC(=O)NC1=O RWQNBRDOKXIBIV-UHFFFAOYSA-N 0.000 claims description 6
- GFFGJBXGBJISGV-UHFFFAOYSA-N Adenine Chemical compound NC1=NC=NC2=C1N=CN2 GFFGJBXGBJISGV-UHFFFAOYSA-N 0.000 claims description 4
- 229930024421 Adenine Natural products 0.000 claims description 4
- 229960000643 adenine Drugs 0.000 claims description 4
- 229940104302 cytosine Drugs 0.000 claims description 4
- 229940113082 thymine Drugs 0.000 claims description 3
- 230000004936 stimulating effect Effects 0.000 claims description 2
- 230000001678 irradiating effect Effects 0.000 claims 1
- 108020004414 DNA Proteins 0.000 description 37
- 238000000034 method Methods 0.000 description 23
- 230000005855 radiation Effects 0.000 description 14
- 239000000126 substance Substances 0.000 description 12
- 238000003776 cleavage reaction Methods 0.000 description 5
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- 230000007017 scission Effects 0.000 description 5
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- 238000004458 analytical method Methods 0.000 description 3
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- 230000007018 DNA scission Effects 0.000 description 2
- ISAKRJDGNUQOIC-UHFFFAOYSA-N Uracil Chemical compound O=C1C=CNC(=O)N1 ISAKRJDGNUQOIC-UHFFFAOYSA-N 0.000 description 2
- 238000000376 autoradiography Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
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- 102000016928 DNA-directed DNA polymerase Human genes 0.000 description 1
- 108010014303 DNA-directed DNA polymerase Proteins 0.000 description 1
- 229910052693 Europium Inorganic materials 0.000 description 1
- 108091028043 Nucleic acid sequence Proteins 0.000 description 1
- 230000000295 complement effect Effects 0.000 description 1
- 238000011109 contamination Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- -1 europium activated barium fluorobromide phosphor Chemical class 0.000 description 1
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Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
- C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
- C12Q1/6869—Methods for sequencing
- C12Q1/6874—Methods for sequencing involving nucleic acid arrays, e.g. sequencing by hybridisation
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
- C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
- C12Q1/6869—Methods for sequencing
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01T—MEASUREMENT OF NUCLEAR OR X-RADIATION
- G01T1/00—Measuring X-radiation, gamma radiation, corpuscular radiation, or cosmic radiation
- G01T1/29—Measurement performed on radiation beams, e.g. position or section of the beam; Measurement of spatial distribution of radiation
- G01T1/2914—Measurement of spatial distribution of radiation
- G01T1/2921—Static instruments for imaging the distribution of radioactivity in one or two dimensions; Radio-isotope cameras
- G01T1/2942—Static instruments for imaging the distribution of radioactivity in one or two dimensions; Radio-isotope cameras using autoradiographic methods
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10S250/00—Radiant energy
- Y10S250/909—Methods and apparatus ancillary to stimulable phosphor systems
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10T—TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
- Y10T436/00—Chemistry: analytical and immunological testing
- Y10T436/14—Heterocyclic carbon compound [i.e., O, S, N, Se, Te, as only ring hetero atom]
- Y10T436/142222—Hetero-O [e.g., ascorbic acid, etc.]
- Y10T436/143333—Saccharide [e.g., DNA, etc.]
Definitions
- This invention relates to a signal processing method for determining base sequence of nucleic acids.
- Maxam-Gilbert method and Sanger-Coulson method are known as typical methods for determining the base sequence of nucleic acids such as DNA and RNA.
- a group containing a radioactive isotope such as 32 P is attached to a chain molecule of DNA or a DNA fragment at one end to label it with the radioactive element and then the bond between the constitutional units of the chain molecule is base-specifically cleaved by a chemical reaction.
- a mixture of the resulting base-specific DNA cleavage products is resolved (developed) through gel electrophoresis to obtain a resolved pattern (not visible) wherein each of the numerous cleavage products is resolved on the gel support medium.
- the resolved pattern is visualized on a radiographic film such as an X-ray film to obtain an autoradiograph thereof as a visible image.
- a radiographic film such as an X-ray film
- the bases in certain positional relationships with the end of the radioactive element-attached chain molecule can be sequentially determined according to the visualized autoradiograph and the applied base-specific cleavage means. In this way, the sequence for all bases of the DNA specimen can be determined.
- the stimulable phosphor sheet comprises a stimulable phosphor and has such properties that when exposed to a radiation, the stimulable phosphor absorbs a portion of radiation energy and then emits light (stimulated emission) corresponding to the radiation energy stored therein upon excitation with an electromagnetic wave (stimulating rays) such as visible light or infrared rays.
- an electromagnetic wave such as visible light or infrared rays.
- the base sequence of the nucleic acids has been conventionally determined by visually judging individual resolved positions of the base-specific cleavage products or the base-specific synthetic products of radioactively labeled nucleic acid (hereinafter referred as to simply base-specific fragments of nucleic acid) on the autoradiograph and comparing them among the resolved rows thereof. Namely, the analysis of the autoradiograph is done by observing the visualized autoradiograph with eyes, and such visual analysis requires great amounts of time and labor.
- the resolved pattern obtained by resolving (developing) radioactively labeled substances on a support medium by electrophoresis or the like is liable to cause various distortion and noise.
- bands which are in the shape of rectangle extending perpendicularly to the resolving direction, tend to be not strictly perpendicular (horizontal) thereto but inclined due to unevenness of a support medium per se such as production of damages or holes on the surface thereof, fluctuation of gel concentration, or contamination thereof with impurities; or deformation of the shapes of slots (sample introducing ports).
- bands resolved and separated after said band are also apt to be observed with the inclination similar thereto. In such case, the resolved positions of the bands are difficult to be accurately determined and the distorted bands causes an error in the determination of the sequence of bands over the resolved rows based on the band positions.
- the present inventor has found that the base sequence of the nucleic acids can be automatically determined with easiness and high accuracy by suitably processing the digital signals corresponding to the autoradiograph in the method for the automatic determination of the base sequence using autoradiography, even when the resolved pattern causes the band distortion.
- the present invention provides a signal processing method for determining base sequence of nucleic acids by subjecting digital signals to signal processing, said digital signals corresponding to an autoradiograph of a resolved pattern which is formed by resolving a mixture of base-specific DNA fragments or base-specific RNA fragments labeled with a radioactive element in one-dimensional direction on a support medium, which comprises steps of:
- the base sequence of a nucleic acid can be simply determined with high accuracy by processing digital signals corresponding to the autoradiograph of the resolved pattern which is formed on a support medium by resolving a mixture of base-specific fragments of the nucleic acid, through a suitable signal processing circuit having a function capable of making correction for the distortion of bands, when the resolved pattern causes the band distortion.
- digital signals are detected in such a manner that plural signals are obtained in the longitudinal direction (direction of the width) of a band and then subjected to the suitable signal processing such as a comparison operation processing, whereby the positions of bands can be accurately determined even when the individual bands are not perpendicular to the resolving direction but inclined.
- the bands are compared and collated over the resolved rows to determine the base sequence of the nucleic acid easily and with high accuracy.
- FIG. 1 is a partial view showing an example of an electrophoretic pattern which locally causes inclination of bands.
- FIG. 2 shows one-dimensional waveforms for the second slot.
- FIG. 3 is an illustrative block diagram of a system which may be employed to practice the invention.
- FIG. 4 is a flow chart of an illustrative program implementing the invention.
- samples employable in the present invention include mixtures of base-specific fragments of nucleic acids such as DNA and RNA labeled with a radioactive element.
- fragments mean portions of a long-chain molecule.
- a mixture of base-specific DNA cleavage products which is a kind of a mixture of base-specific DNA fragments, can be obtained by base-specifically cleaving the radioactively labeled DNA according to the aforementioned MaxamGilbert method.
- a mixture of base-specific DNA synthetic products can be obtained by synthesizing from radioactively labeled deoxynucleoside triphosphates and DNA polymerase by use of DNA as a template according to the aforementioned Sanger-Coulson method.
- RNA is composed of four kinds of bases: adenine, guanine, uracil and cytosine. These substances can be labeled with a radioactive element such as 32 P, 14 C, 35 S, 3 H or 125 I by any of appropriate methods.
- a sample which is a mixture of the base-specific fragments of a nucleic acid labeled with a radioactive element, can be resolved (developed) on a known support medium such as a gel support medium by any of conventional resolving (developing) procedures such as electrophoresis, thin layer chromatography, column chromatography and paper chromatography.
- the support medium on which the radioactively labeled substances are resolved is autoradiographed by means of the conventional radiography using a radiosensitive material or the radiation image recording and reproducing method using a stimulable phosphor sheet.
- the digital signals corresponding to the autoradiograph are then obtained through an appropriate read-out system.
- the support medium and a radiosensitive material such as an X-ray film are placed together in layers at a low temperature of -90 to -70° C. for a long period of time (several tens of hours) to expose the radiographic film.
- the radiographic film is then developed to visualize the autoradiograph of the radioactively labeled substances on the film, and the visualized autoradiograph is read out by using an image read-out system.
- the radiographic film is irradiated with an optical beam and the beam transmitted thereby or reflected therefrom is photoelectrically detected, whereby the visualized autoradiograph can be transformed to electric signals. Further, the electric signals are converted into digital signals corresponding to the autoradiograph through A/D conversion.
- the support medium and the stimulable phosphor sheet are placed together in layers at an ambient temperature for a short period of time (several seconds to several tens of minutes) to store radiation energy radiating from the radioactively labeled substances in the phosphor sheet, whereby the autoradiograph is recorded as a kind of a latent image (energy-stored image) on the prosphor sheet.
- the stimulable phosphor sheet for instance, has a basic structure where a support comprising a plastic film, a phosphor layer comprising a stimulable phosphor such as a divalent europium activated barium fluorobromide phosphor (BaFBr:Eu 2+ ) and a transparent protective film are laminated in this order.
- the stimulable phosphor has characteristics of absorbing and storing radiation energy when irradiated with a radiation such as X-rays and subsequently releasing the stored radiation energy as stimulated emission when excited with visible light to infrared rays.
- the autoradiograph stored and recorded on the stimulable phosphor sheet is read out by using a read-out system.
- the phosphor sheet is scanned with a laser beam to release the radiation energy stored in the stimulable phosphor as light emission and the emitted light is photoelectrically detected, so that the autoradiograph can be directly obtained as electric signals without the visualization thereof. Further, the electric signals are converted into digital signals corresponding to the autoradiograph through A/D conversion.
- the present invention is not limited thereto and digital signals obtained by any other methods can be applied to the signal processing method of the invention, provided that they correspond to the autoradiograph.
- the present invention there may be previously inputted information on the location of each resolved row and the width of band to preset read-out conditions and then conducted scanning at a scanning line density such that each band is traversed by at least two scanning lines in the read-out operation, so as to shorten read-out time and obtain efficiently necessary information.
- the digital signals corresponding to the autoradiograph in the invention also include the thus-obtained digital signals.
- the obtained digital signals D xy comprise a coordinate (x,y) which is represented by a coordinate system fixed to the radiographic film or the stimulable phosphor sheet and a signal level (z) at the coordinate.
- the signal level represents the density of image at the coordinate, that is, the amount of the radioactively labeled substances. Accordingly, a series of the digital signals (namely, digital image data) have information on two-dimensional location of the labeled substances.
- the digital signals corresponding to the autoradiograph of the radioactively labeled substances resolved on a support medium is subjected to signal processing to determine the base sequence of nucleic acid according to the invention described in more detail below.
- Each group of said base-specific DNA fragments is composed of base-specific cleavage products or synthetic products which have various lengths and the same base at terminals.
- FIG. 1 partially shows an autoradiograph of the electrophoretic pattern obtained by electrophoresing the above four groups of the base-specific DNA fragments in four slots, respectively.
- the digital signals corresponding to the autoradiograph are stored temporarily in a memory device of the signal processing circuit (that is, stored in a non-volatile memory unit such as a buffer memory, a magnetic disk, etc.).
- the one-dimensional waveform is a graph with position in the electrophoretic direction as abscissa and signal level as ordinate.
- the detection of the digital signals are carried out by scanning with the laser beam along each lane at such a scanning line density that at least two scanning lines traverse each band as described above (see: FIG. 1; 1: electrophoretic band, 2: scanning line and FIG. 4, step 10)
- the one-dimensional waveform with signal level (z) as vertical axis and position (y) as horizontal axis can be directly prepared for every scanning line.
- FIG. 2 partially shows one-dimensional waveforms a to f for the second slot.
- the waveforms represent a cross-sectional image obtained when bands are cut off along the electrophoretic direction.
- positions (peak positions) where the signal level is maximum are detected, see step 12 of FIG. 4.
- the peak positions are detected by finding out points where the sign of a difference in signal level is inverted (see: FIG. 2; 3: peak position).
- the peak positions detected on the plural one-dimensional waveforms for each band are compared to decide a position of the band, see step 14 of FIG. 4.
- the detected peak positions are consecutively numbered for each waveform and thereby the peak positions having the same number and neighboring on each other can be taken as belonging to the same band.
- the waveform e.g., waveforms c and d in FIG. 2 having high signal levels and one or two more waveforms on each side thereof are considered, and an average position, a maximum position or a minimum position of the peak positions having the same number on these waveforms is calculated.
- A indicates positions of the bands finally decided by taking an average of the peak positions on the waveforms b to e for each band.
- the average of peak positions is usually taken as the band position.
- the maximum of peak positions is preferably taken as the band position.
- the minimum of peak positions may be taken as the band position.
- the band positions can be individually determined even when the bands are inclined.
- the digital signals may be subjected to signal processing for correction therefor before or after the above-described processing for the correction for the band distortion.
- the smiling phenomenon is a phenomenon in which migration distances of the radioactively labeled substances at the both sides of the support medium are shorter than that in the vicinity of the center thereof.
- the smiling phenomenon is caused by heat dissipation effect (so-called edge effect), etc. during the electrophoresis.
- the offset distortion is a phenomenon in which positions of the lanes are wholly deviated from one another and is caused by difference between the slots in the electrophoresis-starting position or time of samples, which is due to the unevenness of the shapes of slots, etc.
- the combining of bands is a phenomenon in which two or three bands are combined together to form one broad band and is caused by the insufficient electrophoresis. Usually, the combined bands tend to be appeared in the upper region of the pattern near the electrophoresisstarting position.
- All the bands are sequenced directly by comparing the decided band positions with each other.
- the sequence can be easily determined on the basis of the fact that two or more bands can not be detected at the same positions of the lanes since a combination of the above four groups of the base-specific DNA fragments is exclusive from each other.
- the four slots (1) to (4) have information on the terminal base of (G), (A), (T) and (C), respectively, so that the substitution of the band sequence with bases corresponding to the slots which the individual bands belong to gives the base sequence of DNA.
- the base sequence of DNA can be obtained as:
- the base sequence of one chain molecule of DNA can be determined.
- the representation mode of the information on the base sequence of DNA is by no means limited to the above-mentioned mode, and other representation modes may be employed optionally.
- the intensity (z') of each band can be together denoted as the relative amount of the radioactively labeled substances, if desired.
- the base sequence of both two chain molecules of DNA can be also represented.
- the information can be also displayed as an image on the basis of the above processed digital signals.
- the original autoradiograph can be displayed as a visualized image.
- investigators themselves can finally determine the DNA sequence on the basis of the display image.
- the signal processing method of the present invention is by no means limited to this combination, and other combinations can be used.
- a combination of (G, G+A, T+C, C) can be used.
- the signal processing method of the invention can be also applied to the mixtures (for instance, a combination of G, A, U, C) of base-specific RNA fragments.
- the correction for the band distortion is not limited to one set of resolved rows of base-specific fragments of a nucleic acid, but can be made on all resolved rows simultaneously resolved on a support medium.
- the information on the base sequence of DNA determined through the above-described signal processing is output from the signal processing circuit, and subsequently transmitted to a recording device directly or optionally via storage in a storage means such as a magnetic disk or a magnetic tape.
- a storage means such as a magnetic disk or a magnetic tape.
- Various recording devices based on various systems can be employed for recording the information, for example, a device for visualizing optically by scanning a photosensitive material with a laser beam, etc., a display means for visualizing electrically on CRT, etc., a means for printing symbols and/or numerals displayed on CRT by means of a video printer, and a means for visualizing on a heatsensitive recording material using thermic rays.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP60181432A JPS6242057A (ja) | 1985-08-19 | 1985-08-19 | 核酸の塩基配列決定のための信号処理方法 |
JP60-181432 | 1985-08-19 |
Publications (1)
Publication Number | Publication Date |
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US4802101A true US4802101A (en) | 1989-01-31 |
Family
ID=16100669
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US06/897,999 Expired - Lifetime US4802101A (en) | 1985-08-19 | 1986-08-19 | Signal processing method for determining base sequence of nucleic acid |
Country Status (4)
Country | Link |
---|---|
US (1) | US4802101A (fr) |
EP (1) | EP0213537B1 (fr) |
JP (1) | JPS6242057A (fr) |
DE (1) | DE3686376T2 (fr) |
Cited By (19)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4958281A (en) * | 1985-10-11 | 1990-09-18 | Fuji Photo Film Co., Ltd. | Signal processing method for determining base sequence of nucleic acid |
US4972325A (en) * | 1986-03-29 | 1990-11-20 | Fuji Photo Film Co., Ltd. | Signal processing method for determining base sequence of nucleic acid |
US4980827A (en) * | 1985-10-11 | 1990-12-25 | Fuji Photo Film Co., Ltd. | Signal processing method for determining base sequence of nucleic acid |
US5121320A (en) * | 1988-10-17 | 1992-06-09 | Hitachi Software Engineering Co., Ltd. | System for reading and displaying an edit-processed DNA pattern |
US5270214A (en) * | 1990-05-30 | 1993-12-14 | The United States Of America As Represented By The United States Department Of Energy | Method for sequencing DNA base pairs |
US5365455A (en) * | 1991-09-20 | 1994-11-15 | Vanderbilt University | Method and apparatus for automatic nucleic acid sequence determination |
WO1997031327A1 (fr) * | 1996-02-26 | 1997-08-28 | Motorola Inc. | Carte personnelle du genome humain et procedes et systemes de fabrication de celle-ci |
US5894589A (en) * | 1995-02-23 | 1999-04-13 | Motorola, Inc. | Interactive image display system |
US5972619A (en) * | 1987-04-01 | 1999-10-26 | Hyseq, Inc. | Computer-aided analysis system for sequencing by hybridization |
US6242180B1 (en) | 1994-10-21 | 2001-06-05 | Affymetrix, Inc. | Computer-aided visualization and analysis system for sequence evaluation |
US6451996B1 (en) | 1987-04-01 | 2002-09-17 | Callida Genomics, Inc. | Method of sequencing of genomes by hybridization of oligonucleotide probes |
US20020155492A1 (en) * | 1990-12-06 | 2002-10-24 | Affymetrix, Inc. | Arrays for detecting nucleic acids |
US20030148328A1 (en) * | 1996-11-05 | 2003-08-07 | Kayyem Jon Faiz | AC methods for the detection of nucleic acids |
US20030150723A1 (en) * | 1996-11-05 | 2003-08-14 | Kayyem Jon F. | Electrodes linked via conductive oligomers to nucleic acids |
US20030175947A1 (en) * | 2001-11-05 | 2003-09-18 | Liu Robin Hui | Enhanced mixing in microfluidic devices |
US20030235853A1 (en) * | 1989-06-07 | 2003-12-25 | Affymetrix, Inc. | Very large scale immobilized polymer synthesis |
US20040175718A1 (en) * | 1995-10-16 | 2004-09-09 | Affymetrix, Inc. | Computer-aided visualization and analysis system for sequence evaluation |
US20050148002A1 (en) * | 1990-12-06 | 2005-07-07 | Affymetrix, Inc. | Sequence of surface immobilized polymers utilizing microfluorescence detection |
US20080237021A1 (en) * | 2007-03-30 | 2008-10-02 | Intermec Technologies Corporation | Keypad overlay membrane |
Families Citing this family (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH0799353B2 (ja) * | 1987-03-31 | 1995-10-25 | 株式会社島津製作所 | 塩基配列決定装置 |
JPH01224657A (ja) * | 1988-03-04 | 1989-09-07 | Hitachi Ltd | 核酸の塩基配列決定装置 |
JP2762451B2 (ja) * | 1988-03-31 | 1998-06-04 | アイシン精機株式会社 | 遺伝子物質の電気泳動パターン分析装置 |
ATE199571T1 (de) * | 1994-12-23 | 2001-03-15 | Imperial College | Automatisches sequenzierungs verfahren |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
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US4524420A (en) * | 1982-08-25 | 1985-06-18 | Core Laboratories, Inc. | Signal processing apparatus |
US4617468A (en) * | 1983-02-24 | 1986-10-14 | Fuji Photo Film Co., Ltd. | Stimulable phosphor sheet with hydrophilic surface |
US4624769A (en) * | 1984-06-29 | 1986-11-25 | Hitachi, Ltd. | Electrophoresis apparatus for nucleic acid fragments |
US4665312A (en) * | 1983-03-31 | 1987-05-12 | Fuji Photo Film Co., Ltd. | Signal detecting method in autoradiography |
US4720786A (en) * | 1985-04-19 | 1988-01-19 | Fuji Photo Film Co., Ltd. | Method of compensating for offset distortion in rows of electrophoretic patterns |
Family Cites Families (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS59182364A (ja) * | 1983-03-31 | 1984-10-17 | Fuji Photo Film Co Ltd | オ−トラジオグラフイ−における信号検出法 |
EP0160948A3 (fr) * | 1984-05-04 | 1989-02-08 | Fuji Photo Film Co., Ltd. | Procédé de traitement d'un signal pour l'autoradiographie |
JPS6118873A (ja) * | 1984-07-06 | 1986-01-27 | Fuji Photo Film Co Ltd | オ−トラジオグラフイ−における信号処理法 |
JPS6285862A (ja) * | 1985-10-11 | 1987-04-20 | Fuji Photo Film Co Ltd | 核酸の塩基配列決定のための信号処理方法 |
-
1985
- 1985-08-19 JP JP60181432A patent/JPS6242057A/ja active Granted
-
1986
- 1986-08-19 DE DE8686111432T patent/DE3686376T2/de not_active Expired - Fee Related
- 1986-08-19 US US06/897,999 patent/US4802101A/en not_active Expired - Lifetime
- 1986-08-19 EP EP86111432A patent/EP0213537B1/fr not_active Expired - Lifetime
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Cited By (38)
Publication number | Priority date | Publication date | Assignee | Title |
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US4980827A (en) * | 1985-10-11 | 1990-12-25 | Fuji Photo Film Co., Ltd. | Signal processing method for determining base sequence of nucleic acid |
US4958281A (en) * | 1985-10-11 | 1990-09-18 | Fuji Photo Film Co., Ltd. | Signal processing method for determining base sequence of nucleic acid |
US4972325A (en) * | 1986-03-29 | 1990-11-20 | Fuji Photo Film Co., Ltd. | Signal processing method for determining base sequence of nucleic acid |
US5972619A (en) * | 1987-04-01 | 1999-10-26 | Hyseq, Inc. | Computer-aided analysis system for sequencing by hybridization |
US6451996B1 (en) | 1987-04-01 | 2002-09-17 | Callida Genomics, Inc. | Method of sequencing of genomes by hybridization of oligonucleotide probes |
US6316191B1 (en) | 1987-04-01 | 2001-11-13 | Hyseq, Inc. | Computer-aided analysis system for sequencing by hybridization |
US5121320A (en) * | 1988-10-17 | 1992-06-09 | Hitachi Software Engineering Co., Ltd. | System for reading and displaying an edit-processed DNA pattern |
US20050170340A9 (en) * | 1989-06-07 | 2005-08-04 | Affymetrix, Inc. | Arrays for detecting nucleic acids |
US20030235853A1 (en) * | 1989-06-07 | 2003-12-25 | Affymetrix, Inc. | Very large scale immobilized polymer synthesis |
US20050148027A1 (en) * | 1989-06-07 | 2005-07-07 | Affymetrix Inc. | Very large scale immobilized polymer synthesis |
US20030003475A1 (en) * | 1989-06-07 | 2003-01-02 | Affymetrix, Inc. | Arrays for detecting nucleic acids |
US20050053928A9 (en) * | 1990-03-07 | 2005-03-10 | Affymetrix, Inc. | Arrays for detecting nucleic acids |
US20030017484A1 (en) * | 1990-03-07 | 2003-01-23 | Affymetrix, Inc. | Arrays for detecting nucleic acids |
US5270214A (en) * | 1990-05-30 | 1993-12-14 | The United States Of America As Represented By The United States Department Of Energy | Method for sequencing DNA base pairs |
US20020155492A1 (en) * | 1990-12-06 | 2002-10-24 | Affymetrix, Inc. | Arrays for detecting nucleic acids |
US20020155491A1 (en) * | 1990-12-06 | 2002-10-24 | Affymetrix, Inc. | Arrays for detecting nucleic acids |
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US7329496B2 (en) | 1990-12-06 | 2008-02-12 | Affymetrix, Inc. | Sequencing of surface immobilized polymers utilizing microflourescence detection |
US20070105131A1 (en) * | 1990-12-06 | 2007-05-10 | Affymetrix, Inc. | Sequencing of surface immobilized polymers utilizing microfluorescence detection |
US20060172327A1 (en) * | 1990-12-06 | 2006-08-03 | Affymetrix, Inc. | Sequencing of surface immobilized polymers utilizing microflourescence detection |
US7459275B2 (en) | 1990-12-06 | 2008-12-02 | Affymetrix, Inc. | Sequencing of surface immobilized polymers utilizing microfluorescence detection |
US20090137419A1 (en) * | 1990-12-06 | 2009-05-28 | Affymetrix, Inc. | Sequencing of surface immobilized polymers utilizing microfluorescence detection |
US20040067521A1 (en) * | 1990-12-06 | 2004-04-08 | Affymetrix, Inc. | Arrays for detecting nucleic acids |
US20050148002A1 (en) * | 1990-12-06 | 2005-07-07 | Affymetrix, Inc. | Sequence of surface immobilized polymers utilizing microfluorescence detection |
US5365455A (en) * | 1991-09-20 | 1994-11-15 | Vanderbilt University | Method and apparatus for automatic nucleic acid sequence determination |
US6242180B1 (en) | 1994-10-21 | 2001-06-05 | Affymetrix, Inc. | Computer-aided visualization and analysis system for sequence evaluation |
US6733964B1 (en) | 1994-10-21 | 2004-05-11 | Affymetrix Inc. | Computer-aided visualization and analysis system for sequence evaluation |
US20050186581A1 (en) * | 1994-10-21 | 2005-08-25 | Affymetrix, Inc. | Computer-aided visualization and analysis system for sequence evaluation |
US6607887B2 (en) | 1994-10-21 | 2003-08-19 | Affymetrix, Inc. | Computer-aided visualization and analysis system for sequence evaluation |
US5894589A (en) * | 1995-02-23 | 1999-04-13 | Motorola, Inc. | Interactive image display system |
US20040175718A1 (en) * | 1995-10-16 | 2004-09-09 | Affymetrix, Inc. | Computer-aided visualization and analysis system for sequence evaluation |
WO1997031327A1 (fr) * | 1996-02-26 | 1997-08-28 | Motorola Inc. | Carte personnelle du genome humain et procedes et systemes de fabrication de celle-ci |
US7056669B2 (en) | 1996-11-05 | 2006-06-06 | Clinical Micro Sensors, Inc. | AC methods for the detection of nucleic acids |
US7125668B2 (en) | 1996-11-05 | 2006-10-24 | Clinical Micro Sensors, Inc. | Electrodes linked via conductive oligomers to nucleic acids |
US20030150723A1 (en) * | 1996-11-05 | 2003-08-14 | Kayyem Jon F. | Electrodes linked via conductive oligomers to nucleic acids |
US20030148328A1 (en) * | 1996-11-05 | 2003-08-07 | Kayyem Jon Faiz | AC methods for the detection of nucleic acids |
US20030175947A1 (en) * | 2001-11-05 | 2003-09-18 | Liu Robin Hui | Enhanced mixing in microfluidic devices |
US20080237021A1 (en) * | 2007-03-30 | 2008-10-02 | Intermec Technologies Corporation | Keypad overlay membrane |
Also Published As
Publication number | Publication date |
---|---|
EP0213537A3 (en) | 1988-09-07 |
EP0213537B1 (fr) | 1992-08-12 |
DE3686376T2 (de) | 1993-01-28 |
JPS6242057A (ja) | 1987-02-24 |
JPH0462344B2 (fr) | 1992-10-06 |
DE3686376D1 (de) | 1992-09-17 |
EP0213537A2 (fr) | 1987-03-11 |
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